Project Summary/Abstract The proposed research will clarify how heritable risks and prenatal and postnatal environments work together with hormonal changes to influence the development of risk for early substance use (SU) and related problems in adolescence. Understanding the development of SU problems is a vital health concern due to the economic costs of dealing with SU related injury, illness, death, crime, and lost productivity. Pathways and interactions by which genes, prenatal exposures, hormones, and key postnatal environmental factors influence the development of SU are not fully understood, in part because studies have not considered them together. The proposed research is innovative by using and expanding an existing prospective longitudinal adoption study, the Early Growth and Development Study (EGDS) to address the dearth of research combining heritable, prenatal, hormone, and postnatal influences. This proposal is timely, directly addressing PA-15-110, by using genetically informative approaches to expand research on the interplay of genetic and environmental factors in the genesis and course ? of substance use disorders and comorbid conditions. The EGDS is a longitudinal study of children adopted at birth and their birth and adoptive parents (N = 561 linked triads). We propose to collect new data into early adolescence on SU milestones and related behaviors, and pubertal development. We will use existing and new data to: (SA1) estimate the unique contributions of heritable risk, prenatal, and postnatal environmental influences on trajectories of child behaviors from infancy to adolescence that increase risk for SU; (SA2) examine the mediating role of prenatal exposures for transmitting heritable influences on trajectories of behavioral risk for SU; (SA3) examine the mediating role of hormone development for transmitting heritable, prenatal and postnatal environmental influences on trajectories of behavioral risk for SU; and (SA4) Examine moderation of heritable, prenatal, and hormone influences by postnatal environments to elucidate the possible interactions among these factors in influencing child risk behaviors and early SU. This study will help to advance knowledge of the development of adolescent SU, to clarify which children are at greater risk for developing SU early in adolescence, and which influences are most salient for SU development given multiple other influences. This prospective, longitudinal, genetically-informed investigation using the EGDS is uniquely poised to achieve these aims, which are critical for gaining a more precise understanding of factors influencing the developmental course of SU that can be used to improve prevention efforts.